Interleukin-6 as an endogenous pyrogen: induction of prostaglandin E2 in brain but not in peripheral blood mononuclear cells

Dinarello, Charles A.; Cannon, Joseph G.; Mancilla, Javier; Bishai, Isis; Lees, Jodi; Coceani, Flavio

doi:10.1016/0006-8993(91)90622-3

Cited by 148 publications

(81 citation statements)

References 33 publications

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“…For example, prostaglandin inhibitors abrogate fever induced by IL-1␤ and IL-6. [106][107][108] Systemic injection of LPS leads to the synthesis of iNOS and COX2 mRNA in cells of the BBB. 51,52,[109][110][111][112] Inhibition of these enzymes attenuates fever, activates c-Fos expression in the brainstem and hypothalamus and activates the HPA axis (upon systemic injection of LPS or IL-1␤).…”

Section: Cytokine Cascadesmentioning

confidence: 99%

Cytokine signals propagate through the brain

et al. 2000

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Interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF␣) are proinflammatory cytokines that are constitutively expressed in healthy, adult brain where they mediate normal neural functions such as sleep. They are neuromodulators expressed by and acting on neurons and glia. IL-1 and TNF␣ expression is upregulated in several important diseases/disorders. Upregulation of IL-1 and/or TNF␣ expression, elicited centrally or systemically, propagates through brain parenchyma following specific spatio-temporal patterns. We propose that cytokine signals propagate along neuronal projections and extracellular diffusion pathways by molecular cascades that need to be further elucidated. This elucidation is a prerequisite for better understanding of reciprocal interactions between nervous, endocrine and immune systems. Molecular Psychiatry (2000) 5, 604-615.

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Section: Cytokine Cascadesmentioning

confidence: 99%

Cytokine signals propagate through the brain

et al. 2000

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“…Because of its similarities to IL-1 signal transduction, IL-18 was initially considered to induce PGE 2 production in PBMC as does IL-1-triggered PGE 2 synthesis in blood monocytes (35) and synovial fibroblasts (15). It was anticipated that IL-18, primarily acting on T and natural killer cells, would induce TNF␣ production with subsequent IL-1␤ and PGE 2 synthesis in monocytes.…”

Section: Discussionmentioning

confidence: 99%

IL-18 binding protein increases spontaneous and IL-1-induced prostaglandin production via inhibition of IFN-γ

Reznikov

Kim

Westcott

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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IL-18 shares with IL-1 the same family of receptors and several identical signal transduction pathways. Because of these similarities, IL-18 was investigated for its ability to induce prostaglandin E 2 (PGE 2 ) synthesis in human peripheral blood mononuclear cells (PBMC), a prominent, proinflammatory property of IL-1. IL-18 was highly active in PBMC by inducing the synthesis of the chemokine IL-8; however, no induction of PGE 2 synthesis nor cyclooxygenase type-2 gene expression was observed in PBMC stimulated with IL-18. In the same cultures, IL-1β induced a 12-fold increase in PGE 2 . Although IL-1β-induced IL-8 synthesis was augmented 3-fold by IL-18, IL-18 suppressed IL-1β-induced PGE 2 production by 40%. The suppressive effect of IL-18 on PGE 2 production was mediated by interferon (IFN)-γ because anti-human IFN-γ-antibody prevented IL-18-induced reduction in PGE 2 . Consistent with these observations, IL-12, a known inducer of IFN-γ, augmented IL-1β-induced IFN-γ but suppressed IL-1β-induced PGE 2 by 75%. IL-18 binding protein (IL-18BP) is a naturally occurring and specific inhibitor of IL-18. When recombinant IL-18BP was added to PBMC cultures, unexpectedly, spontaneous PGE 2 production increased. PGE 2 production was also increased by the addition of IL-18BP to PBMC stimulated with either IL-1β or IL-12 and also in whole blood cultures stimulated with Staphylococcus epidermidis . These studies demonstrate that IL-18BP decreases endogenous IL-18 activity by reducing IFN-γ-mediated responses.

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“…Indeed, the same cytokines that mediate the inflammatory processes are also endogenous pyrogens. 1,2 Interleukin-6 (IL-6), the major mediator of the hepatic acute-phase response, 3 has been shown to have pyrogenic activity in rabbits 4 and is clinically correlated with elevated body temperature in patients with severe burns. 5 Although fever is a common response to infection and inflammatory processes in all vertebrates and is usually assumed to be beneficial to the host, the role of fever as part of the host defense mechanism has not been conclusively established.…”

mentioning

confidence: 99%

Interaction between heat shock and interleukin 6 stimulation in the acute-phase response of human hepatoma (HepG2) cells

1998

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Two characteristic elements of the acute-phase response are an altered pattern of circulating hepatic proteins and fever. Whereas a fever-induced heat shock response could affect expression of acute-phase proteins in the liver, the effects of a modest temperature increase on protein secretion in interleukin-6 (IL-6)-stimulated HepG2 cells were investigated. The response of HepG2 cells to IL-6 stimulation was significantly affected by heat treatment at 40ЊC. Albumin secretion rates, which were reduced by a factor of 2 in response to either heat shock or IL-6 stimulation alone, were down-regulated by a factor of 4 when IL-6 was administered simultaneously with a continuous 40ЊC heat shock. IL-6-induced fibrinogen up-regulation was significantly reduced by heat treatment (P F .01), and secretion rates were indistinguishable from control levels after 2 days (P G .10). Unexpectedly, heat shock at 40ЊC induced a fivefold up-regulation of haptoglobin production in the absence of IL-6. Simultaneous heat shock and IL-6 stimulation caused a synergistic enhancement of haptoglobin expression, with secretion rates increasing up to 30-fold compared with unstimulated control cells. For all three proteins, the interaction between temperature and IL-6 concentration was statistically significant (P F .001). Heat treatment resulted in significant alterations of both the kinetics and sensitivity of IL-6-induced protein synthesis, suggesting a major modification of the mechanism of acute-phase protein regulation at 40ЊC. In summary, the data show that heat shock can significantly modulate the pattern of acute-phase protein expression and that fever may be an important regulatory factor in the acute-phase response. (HEPATOLOGY 1998;28:994-1004.)The acute-phase response, a collective term referring to the constellation of host defense mechanisms induced in response to inflammation, infection, trauma, and certain malignancies, is characterized by drastic metabolic changes in the liver and is often accompanied by fever in the host. Indeed, the same cytokines that mediate the inflammatory processes are also endogenous pyrogens.

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Interleukin-6 as an endogenous pyrogen: induction of prostaglandin E2 in brain but not in peripheral blood mononuclear cells

Cited by 148 publications

References 33 publications

Cytokine signals propagate through the brain

Cytokine signals propagate through the brain

IL-18 binding protein increases spontaneous and IL-1-induced prostaglandin production via inhibition of IFN-γ

Interaction between heat shock and interleukin 6 stimulation in the acute-phase response of human hepatoma (HepG2) cells

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